Androgens, oestrogens and endometrium: a fine balance between perfection and pathology

Abstract

<jats:p>The endometrium is a complex multicellular tissue that is exquisitely sensitive to the actions of sex steroids synthesised in the ovary (endocrine system). Recent studies have highlighted a previously under-appreciated role for local (intracrine) metabolism in fine-tuning tissue function in both health and disease. In this review we have focused on the impact of oestrogens and androgens on endometrial function summarising data from studies on normal endometrial physiology and disorders including infertility, endometriosis and cancer. We consider the evidence that expression of enzymes including aromatase, sulphatase and AKR1C3 by endometrial cells plays an important role in tissue function, and malfunction, and discus results from studies using drugs targeting intracrine pathways to treat endometrial disorders. We summarise studies exploring the spatial and temporal expression of oestrogen receptors (ERalpha, ERbeta and GPER) and their role in mediating the impact of endogenous and synthetic ligands on cross-talk between vascular, immune, epithelial and stromal cells. There is a single androgen receptor and androgens play a key role in stromal-epithelial cross talk, scar-free healing of endometrium during menstruation and regulation of cell proliferation. The development of new receptor-selective drugs (SERMs, SARMs, SARDs) has reinvigorated interest in targeting receptor subtypes in treatment of disorders including endometriosis and endometrial cancer and some show promise as novel therapies. In summary, understanding the mechanisms regulated by sex steroids provides the platform for improved personalised treatment of endometrial disorders as well as novel insights into the impact of steroids on processes such as tissue repair and regeneration.</jats:p>

Cell-Penetrating Peptide and siRNA-Mediated Therapeutic Effects on Endometriosis and Cancer In Vitro Models

“…In parallel, it has to be taken into consideration that during the normal proliferative phase of human menstrual cycle the endometrial layer of the uterus indeed has a high proliferation rate of the cells. This is a normal response to steroid hormones produced by the ovaries in order to rapidly prepare for the prospective pregnancy [ 36 ]. To add, it has been described that endometriosis lesions also exhibit estradiol-dependent proliferation [ 37 ] and, at the same time, ribonucleotide reductase is a crucial enzyme for DNA synthesis and cell proliferation [ 26 ].…”

Endometriosis: Etiology, pathobiology, and therapeutic prospects

“…The classical description of an endometriosis lesion is as a ''piece of tissue'' that resembles the endometrial lining of the uterus (referred to as the ''eutopic endometrium'' in studies comparing its phenotype with the ectopic lesions). The eutopic endometrium is a dynamic multicellular steroid-responsive tissue with epithelial cells supported by a stromal compartment containing a rich blood supply and fluctuating populations of immune cells, the luminal portion of which breaks down and is shed during menstruation (Gibson et al, 2020;Wang et al, 2020). Studies on the etiology of endometriosis lesions have benefited from an improved understanding of the regulation of endometrial repair combined with interrogation of primate and rodent models using ''menstrual tissue'' to generate artificial lesions (Critchley et al, 2020;Saunders, 2020).…”

“…In the normal endometrium expression of receptors that bind to estrogens (ERa, ERß, and GPER1), androgens (AR), progestins (PRA and PRB), or glucocorticoids (GR and MR) are both cell-specific and menstrual cycle phase-dependent (Gibson et al, 2020;Yilmaz and Bulun, 2019). Disregulation of expression of PR, including altered epigenetic programing of the PR promoter has been detected in endometrium and lesions from women with endometriosis (Yilmaz and Bulun, 2019).…”

Insights Gained from Genomic Studies on the Role of Sex Steroids in the Aetiology of Endometriosis

“…The human endometrium is a complex multicellular tissue that is exquisitely sensitive to the actions of sex steroids with cycles of proliferation, differentiation breakdown, shedding and repair orchestrated by changes in circulating concentrations of endocrine hormones secreted by the ovaries (Critchley et al, 2020;Gibson et al, 2020). The action of steroids, including oestrogens, progestins and androgens is mediated by receptors notably those encoded by genes (ESR1, ESR2, PR, AR) that are members of a large family of ligand-activated transcription factors (Mangelsdorf et al, 1995).…”

“…The action of steroids, including oestrogens, progestins and androgens is mediated by receptors notably those encoded by genes (ESR1, ESR2, PR, AR) that are members of a large family of ligand-activated transcription factors (Mangelsdorf et al, 1995). Detailed evaluation of cell specific patterns of immunoexpression of oestrogen receptors alpha (ESR1) and beta (ESR2) (Critchley et al, 2001;Critchley et al, 2002), progesterone receptor subtypes (PRA, PRB) (Gellersen and Brosens, 2003;Wang et al, 1998) and androgen receptors (Gibson et al, 2020) have been conducted. These studies combined with evidence from cell-based assays and mouse models has highlighted a key role for ESR1 in regulation of endometrial cell proliferation and stromalepithelial cell signalling (Winuthayanon et al, 2010;Winuthayanon et al, 2017).…”